N2-substituted hydrazides as monoamine oxidase inhibitors



United States Patent N -SUBSTITUTED HYDRAZIDES AS MONO- AMINE OXIDASE INHIBITORS Paul Coirre, Blvd. du MontparnassaParis, France No Drawing. Filed July 5, 1961, Ser. No. 121,843 Claims priority, application France, July 15, 1960,

5 Claims. a. 260-559) The present invention relates to N -substituted hydrazides, which are inhibitors of the mono-amine-oxidase intended notably for psychiatric and cardiologic use and ob tained by synthesis of a hormone of vegetable growth,

also called acid for regulating the growth of vegetables, with a radical promoting the inhibition of the mono-aminooxidase.

This invention is concerned more particularly with the isopropyl-hydrazide of the p-chlorophenoxy-acetic acid which may be obtained by synthesis of a hormone of vegetable growth, the p-chlorophenoxyacetic acid, with the isopropyl-hydrazide radical.

of vegetable growth, notably:

The 2,4-dichlorophenoxyacetic acid The 2,4,S-trichlorophenoxyacetic acid The methyl-Z-chloro-4-phenoxyacetic acid It is also concerned with the synthesis of other hormones with the same isopropyl-hydrazide radical, which yields substances having the same mono-amine properties.

oxidase inhibiting Other radicals than the isopropyl-hydrazide may be used for synthetizing from hormones of vegetable growth substances promoting the inhibition of the mono-aminoxidase, provided that these radicals contain at least the The general formula NH-NH group in their formula.

of these substances, which are the N -substituted hydrazides according to the invention is:

l il

wherein X is selected from the group consisting of H, Cl and CH X is Cl, X is seleced from the group consist ing of H and Cl, and R is isopropyl.

The formulae of the isopropyl-hydrazide of the p-chlorophenoxyacetic acid and of its derivatives for which R in the hereinabove formula is the isopropyl radical, are as follows: Isopropyl-hydrazide of p-chlorophenoxyacetic acid rr rs z z In the following formulae R represents the radical Isopropyl-hydrazide of 2,4-dichlorophenoxyacetic acid:

Isopropyl-hydrazide of 2,4,S-trichlorophenoxyacetic (ll-GR; onn mmoi acid:

3,193,578 Patented July 6, 1965 "ice Isopropyl-hydrazide of 2 methyl-4-chloro-phenoxyacetic acid:

PHYSICO-CHEMI CAL CHARACTERS OF COMPOUND I (a) Colorless crystals Melting point: 194 F.- -197.6' F.

Moderately soluble in distilled water in the cold state: 1 part per 1000 parts; much more soluble in the heated state: 1 part per 300 parts. The solubility is not appreciably influenced by acidification or alkalinisation.

Solubility in 95-alcohol: 1 part in 50 parts.

Soluble in chloroform and acetone.

Scarcely soluble in ethyl ether.

Insoluble in petroleum ether.

(b) Liebermann-Burchard test.-z'mmediate wine-color turning to light dull green when heated in a water bath METHOD OF PREPARING COMPOUND I (1) Ethyl p-chlorophenoxyacetate m-Qoomcoocnzn 49 grams of p-chlorophenol are condensed with 47 grams of ethyl chloroacetate in a basic medium (sodium ethylene) at boiling temperature. After purification, 35.7 grams of solid product melting at 45 C. (113 F.) are obtained, with a 44% yield.

(2) p-Chloro-phenoxyacetic hydrazide or-Q-ocmoorsnrrn, 0.11.011

The ethyl p-chloro-phenoxyacetate is treated with a small hydrazine excess in an alcoholic medium and under such conditions that the condensed liquid flows back, at the boiling temperature. The hydrazide crystallizes after cooling. From 17.1 grams of ester 13.8 grams of hydrazide are obtained. M.P.=158159 C. (316-318" F). Yield=86.7%.

(3) Acetonic hydrazone of p-chloro-phenoxyacetic acid By reflux heating at boiling temperature during 12 hours with a large excess of acetone, the hydrazide pro? vides hydrazone with @a nearly quantitative yield.

M.P.=144145 C. (292-294 F.). Calc. C, 54.88%

(theor. 54.36), Calc. H, 5.40% (theor. 5.62).

I (4) N-isopropylhydl azia'e ofp-chlorophenoucyacetic acid . on, By catalytic reduction in the presence of platinum oxide according to the Adams process in an alcoholic medium (under a pressure of 2 rn. of water) 3 grams of product are obtained from 5 grams of hydrazone. Yield=60%. The aggregate yield is 23%.

The other 'N -substituted hydrazides according to the V invention are obtained by a similar process, starting from the convenient phenol and utilizing in the step (3) of the process the appropriate ketone or aldehyde in view of providing through the step (4) the desired R radical.

PHARMACOLOGICAL PROPERTIESVOF COMPOUND 1 1) Lethal dose 50 The lethal dose 50 determined in 24 hours in a mouse is 177.5 mg./kg. through the intra-peritoneal way.

(2) Criteria of pharmacological activity The product acts asfan'inhibitor of the monoamineoxidase.

a As a matter of fact, V V

(a) In a mouse, .10 mg./kg. administered as an intraperitoneal injection (I.P.) dose, 1'h0ur,;4 hours or 18 hours before the reserpine (0.75 mg./kg. as a sub-cutaneous (S.C.) injection), counteracts the 'ptosis'normally caused by the reserpine. e V

(b) In a mouse, when'administered by LP. 1 hour be- 7 fore 100 mg/kg. of 5 hydroXy-tryptopha'n (throughthe same Way) at the dose of 1 mg./kg., it increases the motorial activity, it produces an excitation syndrome in 80 animals out of 100 at the dose of 5 mg./kg. and i 100% of mice at the dose of 25 mg./ kg.

(c) In a rat,' the I.V. (intravenous) administration of tryptamine (5 rug/kg.) produces convulsions in 80% of- I the cases, 1 hour and 4 hours after the LP; administration of 25 mg./ kg. of the product, in 100% of the cases4 hours after 50 mg./kg. (LR), in 100% of the cases 4 hours after the oral administration of 10 mg./kg., in of cases 18 hours after the oral administration of 10 mg./ kg. (d) In a rabbit, administered per os, at the, dose of- 75 mg./kg. 3 hours before, it counteracts the effects I of reserpine and causes a syndrome of excitation attended by mydriasis and .hyperpyrexia.

The same efiect is obtained by I.V. of 25 mg./kg.,,1

hour before the injection of reserpine. I I

The. product may therefore be considered as an inhibitor of mono-amine oxidase of whichthe activity is, with respect to isopropyl-hydrazide of isonicotinic acid (Marsilid), 6 to 25 times greater in the 5 hydroXy-tryp tophan test with a mouse, 4 times greater in the reserpine test with a rabbit, 3 times greater in the tryptamine test I V 651 with a rat. 1

It is an inhibitor of the monoarnineoxidase, and its efiects are both rapid (1 hour) and lasting (18 hours at 1e ast).-

(3) Action exerted on the cardiovascular system In a chloralosed dog the product (10 mg./kg.) does not produce appreciable variations in the arterial pres sure, in spite of a reduction in the cardiac output, due to an increase in the peripheral vascular resistance.

On, the other hand, it reduces the aggregate cardiac Benedict apparatus.

eifort and the oxygen consumption measured with the These effects on the cardio-vascular system distinguish the product from the other hitherto known inhibitors of the monoamine-oxidase, such as Marsilid and Tersavid.

THERAPEUTIC APPLICATIONS OF COMPOUND I Inhibitor of the monoami'ne-oxidas'e which is effective in the following cases: I

' I (A) Psychiatry I DEPRES-SIVE SYNDROME I Melancholic, reactive and neutrotic depressions, in-

volutional and senile depressions, depressions by exhaustion or asthenia.

Maniaco-depressive psychosis, in depressive phase. Failures and insufiicient results,consolidation of the therapeutic effect, prevention and relapses in convulsive- Angors of decubitus. 7 Angors of persons suffering from high blood pressure.

OTHER Forms orr'Aneons Arterial hypertension. Intermittent limping due to arthritis in f c Otherindications 'Loss of weight, of appetite; A

the lower limbs.

' I Bacteriostatic and bacteriolytic action against the bacilli of Koch.

Se'nescence. Rheumatic arthritis.

OF THERAPEUTIC APPLICATION (a) Psychiatric applicati0n.Reactive depression: 20 mg. per 0s per day during one week, 10 mg. the following two weeks. The symptoms disappeared.

' (b) Cardiologic applicati0n.-Angor of efifort: 30 mg.

per day per os, the pain disappeared after 2 days. Maintenance treatment: 10 mg. per day.

form of tablets containing (c) Other applications.Loss of weight: 10 mg. per

a day per os, recovery of appetite and weight.

The treatment may be administered by oral route in the .0 1 g. of product and .09 gram of excipient. I a i What I claim is:

1. An N -substituted hydrazide of the formula.

= wherein X is selected from they group consisting of H,

Cland CH X is Cl, X is selected from the group consisting of H and Cl, and R is isopropyl.

2. Isopropyl -hydrazide of pchlorophenoxyacetic acid, 3. Isopropyl-hydrazide of 2,4-dichlorophenoxyacetic acid. 7

4. Isopropyl-hydrazide of 2,4,5-trichlorophenoxyacetic acid. I H e 5. Isopropyl-hydrazide of 2-methyl4-chlorophenoxyacetic acid.

References Cited by the Examiner UNITED STATES PATENTS OTHER REFERENCES Baltazzi et a1.: Compt. rend., vol. 241, pp. 633-5 Biel et a1.: Jour. Am. Chem. Soc., vol. 81,'pp. 2805-13 (1959).

Byrkit et a1.: Ind. Eng. Chem., vol. 32, pp. 1862-1865 (1950).

Thompson et a1.: Botanical Gazette, vol. 107 p. 494 (1946).

W-iley et a1.: Jour. Org. Chem, Vol. 24, pp. 1925-8 (1959).

Zeller et a1.: Annals of New York Academy of Science, vol. 80, article 3, pp. 555-567, September 17, 1959.

WALTER A. MODANCE, Primary Examiner.

DUVAL MCCUTCHEN, NICHOLAS S. RIZZO,

FRANK CACCIAPAGLIA, JR., Examiners. 

1. AN N2-SUBSTITUTED HYDRAZIDE OF THE FORMULA. 